There is interest in the possible health benefits of tea against chronic diseases, including cancer. This proposal tests the hypothesis that the inhibitory mechanisms of tea in the GI tract involve the beta-catenin/Apc pathway and expression of beta-catenin/Tcf target genes. Most of the work uses a rat model of colon cancer in which the heterecyclic amine -amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine (PhIP) or 1,2-dimethylhydrazine (DMH) are the initiating agents. Other studies in humans, Apc rain mice, and rainbow trout examine inhibition by tea according to the following aims: Aim 1. BLOCKING EFFECTS OF TEA - 1A. Compare the efficacy of white tea and green tea, and their major constituents, as blocking agents against PhIP-induced aberrant crypt foci (ACF) and colon tumors in the rat. 1B. Examine during the initiation phase the spectrum and frequency of Ctnnbl (beta-Catenin) and Apc mutations in ACF and colon tumors after tea treatment. 1C. Demonstrate a protective effect of tea, decaffeinated tea, caffeine and chlorophyllin in people consuming a dietary-relevant dose of PhlP. Aim 2. SUPPRESSING EFFECTS OF TEA - 2A. Compare the efficacy of white tea and green tea during the post-initiation phase of PhlP- and DMH-induced colon carcinogenesis. 2B. In the tumors from 2A, examine the spectrum and frequency of Ctnnbl and Apc mutations, and the expression of beta-catenin and beta-catenirdTcf/Lef target genes (cyclin D1, c-jun, c-myc). 2C. In Apc min mice, show that tea suppresses intestinal tumorigenesis via downregulation of beta-catenin. 2D. Using the trout methylazoxymethanol acetate model, examine the dose-response for tumor suppression by tea, caffeine, and EGCG. Aim 3. BLOCKING AND SUPPRESSING MECHANISMS - 3A. Examine blocking mechanisms of tea, focusing on (i) degradation of ultimate carcinogens, (ii) inhibition of CYP1A2+NAT, and (iii) induction of UDPGT. 3B. In human colorectal cell lines and cells expressing mutant beta-catenins (i) show that tea downregulates beta-catenin and beta-catenin/Tcf target gene expression, (ii) examine the relative efficiency of phosphorylation and ubiquitination of beta-catenin, and assembly of beta-catenin/Tcf on target genes, in the presence of tea, (iii) demonstrate that beta-catenilg/Tcf-mediated activation of c-jun and cyclin D1 can be overcome by inhibitory actions of tea on AP-1 and CDK's, and (iv) examine the dose-response for cell cycle attest versus apoptosis in cells expressing wt and mutant beta-catenins.